Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial

Background Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. Methods In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon’s two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. Results Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. Conclusions Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. Trial registration ClinicalTrials.gov (NCT 04401800). Supplementary Information The online version contains supplementary material available at 10.1186/s12916-024-03356-5.


Background
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancerrelated deaths worldwide [1].The majority of HCC (approximately 72%) are diagnosed in Asia, with hepatitis B virus (HBV) infection being the most common etiology of HCC [2,3].Despite advancements in early detection, most patients with HCC still present with advanced disease, which limits the opportunity for radical treatment.
Globally, tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib are recommended as first-line treatments for unresectable HCC (uHCC) [4,5].However, the clinical benefits with TKIs were limited due to the unsatisfying objective response rates (ORRs) (for instance, 2% of sorafenib in SHARP study, 18.8% of lenvatinib in REFLECT study) [4,5].More therapeutic options are needed to expand the patient population that could benefit from TKIs.In recent years, immuno-oncology therapies, such as immune-checkpoint inhibitors (ICIs), have reshaped the treatment landscape for advanced HCC.Combining an ICI with a TKI is a promising combination strategy as TKIs may have effects on the vascular endothelial growth factor receptor (VEGFR) and other kinases that may modulate the activity of ICIs [6][7][8].The global LEAP-002 study investigated the efficacy and safety of lenvatinib plus pembrolizumab as a firstline treatment in uHCC patients [9].Though it failed to achieve its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) in the global intent-to-treatment population, recent subgroup analysis revealed encouraging median OS (26.3 vs 22.4 months; hazard ratio [HR] 0.727; 95% confidence interval [CI], 0.552-0.958)and PFS (8.3 vs 6.5 months; HR 0.710; 95% CI, 0.556-0.907)benefit trend compared with lenvatinib alone in Asian population [10], suggesting potential benefits of this combination strategy in Asian patients with a high incidence of HBV-related etiology.Furthermore, a retrospective real-world study in China reported that lenvatinib plus programmed death-1 (PD-1) inhibitors treatment showed considerable overall survival of 17.8 months in uHCC patients not restricted to first-line therapy [11].Taken together, these findings suggest that lenvatinib plus a PD-1 inhibitor is a promising treatment strategy for uHCC patients in China.However, there is no published study prospectively exploring the efficacy and safety of tislelizumab in combination with lenvatinib in the first-line setting.
Tislelizumab is a monoclonal antibody with high affinity and binding specificity for PD-1, which was designed to minimize binding to Fcγ receptors on macrophages to limit antibody-dependent cellular phagocytosis, a potential mechanism contributing to anti-PD-1 therapy resistance [12].In a global randomized phase 3 study (RATIONALE-301), single-agent tislelizumab demonstrated clinically meaningful OS benefit that was noninferior to sorafenib (median OS, 15.9 vs 14.1 months; HR 0.85; [95.003%CI, 0.71 to 1.02]) with a favourable safety profile as a first-line treatment option for patients with uHCC [13].We performed a phase 2 study (BGB-A317-211) to explore the efficacy and safety of tislelizumab in combination with lenvatinib as first-line treatment in Chinese patients with unresectable locally advanced or metastatic HCC.

Study design and participants
BGB-A317-211 was a prospective, multicenter, openlabel, single arm, phase 2 study evaluating tislelizumab plus lenvatinib as first-line treatment in patients with uHCC, conducted in 9 sites across China.This study consisted of a safety run-in phase and an expansion phase (Additional file 1: Fig. S1).Study subjects received intravenous tislelizumab 200 mg on day 1 for a 21-day treatment cycle, in combination with lenvatinib 12 mg (body weight ≥ 60 kg) or 8 mg (body weight < 60 kg) orally taken once daily.The treatment dosage was chosen referring to the phase 1b study KEYNOTE-524, which showed manageable safety profile of anti-PD-1 antibody (pembrolizumab) plus lenvatinib with the combination dose following prescription instructions of each drug [14].During the study design, tislelizumab had been approved in China at a dose of 200 mg intravenously every 3 weeks, however the safety profile of its combination with lenvatinib in HCC had not been evaluated before, therefore, a safety run-in phase (Additional file 2: Supplemental methods) was designed to further ensure patients' tolerance of the present combination.
Treatment was continued until immune confirmed disease progression (iCPD) assessed by immune Response Evaluation Criteria in Solid Tumors (iRECIST), development of unacceptable toxicity, death, withdrawal of consent, or completion of 12 months treatment.Patients who completed 12 months of treatment without iCPD and were deemed to still benefit from the study treatment based on investigator assessment were allowed to continue receiving tislelizumab.
Eligible patients were aged 18-70 years with histologically or cytologically confirmed unresectable locally advanced or metastatic HCC who had no prior systemic therapy.Key inclusion criteria included a Barcelona Clinic Liver Cancer (BCLC) Stage C or B disease, Child-Pugh A classification for liver function, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1, no tumor thrombus involving the main trunk of the portal vein or inferior vena cava, and a life expectancy of ≥ 3 months.Patients were excluded if they had any known brain or leptomeningeal metastases.Detailed inclusion and exclusion criteria are available at ClinicalTrials.gov(NCT 04401800).
The study was approved by the institutional review board or ethics committee for all participating centers and was conducted in accordance with the principles of the Declaration of Helsinki.Written informed consent was obtained from all participants.

Outcomes and Clinical Assessments
Tolerability and safety of the combination were initially assessed by evaluating dose-limiting toxicities (DLTs) based on hematology and non-hematology toxicities in safety run-in phase (Additional file 2: Supplemental methods).The primary endpoint was the confirmed ORR by RECIST v1.1 per independent review committee (IRC).ORR was defined as the proportion of patients with complete response (CR) or partial response (PR) as their best overall response.Secondary endpoints included safety and tolerability, IRC-assessed ORR per mRECIST and iRECIST, IRC-assessed duration of response (DoR; time between first CR or PR and disease progression [PD] or death), disease control rate (DCR; proportion of patients with a best overall response of CR, PR or stable disease [SD]), and PFS (time from first dose of study medication to PD or death) per RECIST v1.1, mRECIST and iRECIST.Investigator-assessed ORR, DoR, DCR, and PFS per RECIST v1.1, mRECIST and iRECIST were also secondary endpoints.OS was an exploratory endpoint, which was defined as the time from first dose of study medication to death.
Tumor radiographic assessments were performed at baseline, every 6 weeks in the first year of treatment, and every 9 weeks thereafter.Adverse events (AEs) were classified based on Medical Dictionary for Regulatory Activities (MedDRA) Version 25.0 and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Statistical analyses
An overall sample size of 60 patients was planned to test the statistical hypothesis for this study.Based on Simon's two-stage design, the study had about 95% power to detect a statistically significant difference of ORR (assessed based on RECIST v1.1 by IRC) in tislelizumab plus lenvatinib (expected to be 40%, referring to the ORR of 36% for lenvatinib plus pembrolizumab in the study KETNOTE-524 [14]), compared with a historical control of 18.8% (referring to the ORR of lenvatinib monotherapy from REFLECT study [5]) with 1-sided alpha as 0.025.Within the first 30 patients (including the 6 patients from the safety run-in phase and 24 patients from the expansion phase) in the efficacy evaluable analysis set (EAS), > 6 responders (CR or PR) were needed in the interim analysis (n = 30) for the study to continue.If within the final 60 patients in the EAS, ≥ 18 responders were observed, statistical superiority to a historical control of 18.8% would be claimed under the settings.The sample size was estimated using R 4.1.2(Additional file 2: Supplemental methods).Considering potential dropouts and actual enrolment conducted simultaneously in multiple sites, the study allowed to include no more than 6 additional patients.
Safety analyses were performed in the safety analysis set (SAS), which included all patients who received at least one dose of tislelizumab or lenvatinib.The EAS included all patients from the SAS who had measurable disease at baseline (per RECIST v1.1) and at least one evaluable post-baseline tumor assessment unless treatment was discontinued for disease progression or death before the first assessment.All efficacy analyses were conducted in the EAS.
Descriptive statistics were used to summarize the data.The continuous and categorical variables were expressed as median (range) and number (percentage), respectively, unless otherwise specified.ORR and DCR were calculated with 95% CIs estimated using the Clopper-Pearson method.Time-to-event variables (DoR, PFS and OS) were estimated using the Kaplan-Meier method, and median values were presented with 95% CIs calculated by the Brookmeyer-Crowley method.PFS and OS rates at 6 months or 12 months were calculated using the Kaplan-Meier method, and their 95% CIs were calculated by the Greenwood formula.All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
As of December 16, 2022, the median follow-up duration was 15.7 months (range, 0.9-27.4).One patient was still receiving study treatment (last cycle of treatment).The median treatment duration of tislelizumab was 11.0 months (range, 0.7-11.9).The median treatment duration of lenvatinib was 11.1 months (range, 0.3-12.1).Overall, 63 (98.4%) patients discontinued study treatment.The primary reason for treatment discontinuation was completion of the planned 12-month study treatment (n = 33, 51.6%).In this study, 28 patients continued to receive study treatment after progression per RECIST v1.1, with a median post-progression treatment of 1.5 months (range, 0.1-10.6).During the postprogression treatment period, 6 patients had target lesions shrinkage compared with baseline and had no new lesions, and of which 1 underwent subsequent curative surgery.Data on subsequent anticancer medications during survival follow-up are summarized in Additional file 3: Table S1.

Safety run-in phase
No DLTs were observed in the first 6 patients of the safety run-in phase.Therefore, the study combination was administered as per the planned dosage consistently throughout the entire study with lenvatinib 12 mg (body weight ≥ 60 kg) or 8 mg (body weight < 60 kg) orally taken once daily and intravenous tislelizumab 200 mg on day 1 for a 21-day treatment cycle.

Efficacy
There were 23 responders per RECIST v1.1 assessed by IRC in the first 60 patients of the EAS, which was more than the preset threshold of 18 responders based on the Simon's two-stage design, indicating that statistical superiority of the study combination therapy over historical control lenvatinib monotherapy was achieved (p = 0.0003).
Serious adverse events (SAEs) were reported in 11 (17.2%)patients; 7 (10.9%)experienced treatment-related SAEs.During the study, 3 (4.7%)deaths occurred.Two deaths were reported as unrelated to study treatments.One death was reported as treatment related.This patient received one dose of tislelizumab and 8 days of lenvatinib and died due to respiratory failure.Death was attributed to disease progression and study treatment.TRAEs leading to treatment discontinuation occurred in 3 (4.7%)patients.TRAEs led to treatment modification in 35 (54.7%) patients.

Discussion
In this open-label, multi-center, phase 2 trial, the combination of tislelizumab and lenvatinib demonstrated promising clinical efficacy in patients with uHCC who had received no prior systemic therapy.The study showed statistical superiority of tislelizumab plus lenvatinib compared with historical data of the lenvatinib arm from the phase 3 REFLECT study [5] in the firstline setting in uHCC patients, with a confirmed ORR of 38.7% per RECIST v1.1 by IRC review.Objective response was observed across subgroups.After a median follow-up duration of 15.7 months, tislelizumab plus  The median OS was not reached, and 1-year OS rate was 88.6% (95% CI, 77.7-94.4).The combination was generally well tolerated, and the safety profile was consistent with tislelizumab or lenvatinib administered alone.
The IMbrave 150 study demonstrated atezolizumab combined with bevacizumab resulted in superior OS and PFS outcomes compared with sorafenib, supported by an improved ORR of 30% and a DCR of 74% by RECIST 1.1 with a median DoR of 18.1 months [15].Current study revealed a confirmed ORR of 38.7% for tislelizumab and lenvatinib combination therapy, with a DCR of 90.3% and a durable DoR (not reached).These results were similar to the results observed in studies of other combinations of ICIs with TKIs in the first-line setting (Additional file 3: Table S3) [9,[14][15][16], such as CARES-310 (camrelizumab plus rivoceranib: ORR 25%, DCR 78%) [16] and LEAP-002 (pembrolizumab plus lenvatinib: ORR 26.1%, DCR 81.3%) [9].Median PFS was 8.2 months per RECIST v1.1 by IRC and 9.6 months by investigator review in current study, which was similar with that reported in large phase 3 trials, with PFS ranging from 5.6 to 8.2 months [9,16,17].The efficacy of tislelizumab plus lenvatinib was close to previous phase 3 trials of other combinations as firstline therapy for uHCC.
In this study, the combination therapy of tislelizumab plus lenvatinib was generally well tolerated with no new or unexpected toxicities.The combination showed safety profile consistent with profiles of each individual agent as reported in previous studies [5,13,18], and with other combinations with ICIs and anti-VEGFR antibodies or targeted therapies (Additional file 3: Table S4) [9,[14][15][16].Notably, grade ≥ 3 TRAEs occurred in only 28.1% of patients with study treatment, which was numerically lower than the rates observed with other combinations (atezolizumab plus bevacizumab in IMbrave 150, 43% [15]; pembrolizumab plus lenvatinib in LEAP-002, 63% [9]; camrelizumab plus rivoceranib in CARES-310, 81% [16]), indicating that tislelizumab plus lenvatinib may present a favourable safety profile.However, it is important to interpret these results with caution considering the different duration of treatment, the limited sample size of the current study and indirect comparison.
While LEAP-002 did not demonstrate statistical superiority of pembrolizumab with lenvatinib over lenvatinib alone, combination treatment led to numerically better results in key endpoints, especially in the subgroup of patients with HBV etiology, which supports clinical value of ICI plus TKI combination in treatment of uHCC.Designing the current study, it was assumed that tislelizumab plus lenvatinib combination might provide larger OS benefit than tislelizumab monotherapy.In this study, the 12-month OS rate was 88.6% (median OS, not reached), which was numerically higher than that from RATIONALE 301 Chinese population (56.6%) [19], indicated that there might be a trend towards improved OS rate with this combination.Taken together, these results indicated that tislelizumab plus lenvatinib could be a promising therapeutic option in the first-line treatment of uHCC with encouraging efficacy and tolerability.
In addition to RECIST v1.1 and mRECIST, we also utilized iRECIST as a method to assess tumor response in this study.This approach allows for the identification of atypical responses, such as delayed responses that may occur after pseudoprogression, thereby potentially preventing early treatment discontinuation due to pseudoprogression [20].In this study, 6 patients who remained Table 3 Frequency of AEs (N = 64) Data are presented as n (%).TRAEs at any grade occurring in ≥ 10% of patients are listed.No grade 5 adverse events occurred among TRAEs reported at an overall frequency of ≥ 10%.imAEs occurring in ≥ 1 patient.Data are listed in order of decreased frequency of any grade TRAE.AEs Adverse events, TRAEs Treatment-related adverse events, imAEs Immune-mediated adverse events on study treatment after iUPD had target lesions shrinkage compared with baseline and had no new lesions, of which 1 received curative surgery subsequently, suggesting that the utilization of iRECIST may benefit some patients by preventing early withdrawal from a potentially effective treatment.
The study has several limitations.Firstly, although the study was designed based on predefined statistical assumptions and sample size calculation, the conclusion on the superiority of the combination than lenvatinib monotherapy from REFLECT study needs cautions based on its single-arm design.Though the latest data of lenvatinib arm from LEAP-002 study demonstrated longer OS and PFS than REFLECT, the ORR was similar, and REFLECT study was the only phase 3 study could be referred as a historical control when the present study was designed.Secondly, the design of maximum treatment period of 12 months might be insufficient for patients who still presenting controlled disease.However, in this study, the continued use of tislelizumab was allowed for patients who completed 12 months of treatment without iCPD and were deemed to still benefit from the study treatment based on investigator assessment.Thirdly, the study only included patients from China, with a quite large proportion (90.6%) of HBV-related HCC.Further verification of the benefits of the combination of tislelizumab plus lenvatinib for HCC patients is warranted in large-scale controlled studies including patients of other etiology.

Conclusions
This phase 2 trial demonstrated that the combination of tislelizumab and lenvatinib was statistically superior compared with historical ORR data of lenvatinib in the first-line treatment of uHCC patients.This combination led to promising PFS and OS rates and was generally well tolerated.
and with the Helsinki Declaration.All procedures involving human subjects/ patients had been approved by the ethics committees of each study site, including the ethics committee of the Sun Yat-sen University Cancer Center

Consent for publication
All patients had provided informed consent for the participants in the study and publication of any associated data.

Fig. 1
Fig. 1 Best percentage change from baseline in sum of diameters of target lesions per RECIST v1.1 by a IRC review and b Investigator review (N = 62).IRC = Independent Review Committee, RECIST = Response Evaluation Criteria in Solid Tumors, PD = progressive disease, SD = stable disease, PR = partial response, CR = complete response

Table 1
Patient demographics and baseline characteristicsData are presented as n (%) unless otherwise indicated.AFP Alpha-fetoprotein, BCLC Barcelona Clinic Liver Cancer, ECOG Eastern Cooperative Oncology Group, HBV Hepatitis B virus, HCC Hepatocellular carcinoma, TACE Transarterial chemoembolization, TE Transarterial embolism

Table 2
Tumor response by IRC and investigator review per RECIST v1.1, mRECIST and iRECIST (EAS, N = 62) a 95% CI was estimated using the Clopper-Pearson method.b One patient received 1 dose of tislelizumab and 8 days lenvatinib and died with confirmed clinical disease progression before the first radiological assessment.IRC Independent Review Committee, RECIST Response Evaluation Criteria in Solid Tumors, mRECIST Modified RECIST, BOR Best overall response, CR Complete response, PR Partial response, PD Progressive disease, SD Stable disease, iRECIST Immune RECIST "i" indicates immune responses assessed using iRECIST, iBOR = BOR, iCR = CR iPR = PR iSD = SD, iUPD Unconfirmed disease progression, iCPD Confirmed disease progression, DCR Disease control rate, EAS Efficacy evaluable analysis set, CI Confidence interval, n/a Not applicable, NE Not evaluable